Methods for minimizing thioamide impurities

ABSTRACT

Methods for minimizing the formation of thioamide compounds using decoy agents during reactions, such as thionations of carbonyl compounds containing nitrite groups, are provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the priority of U.S. provisionalpatent application No. 60/560,403 filed Apr. 8, 2004.

BACKGROUND OF THE INVENTION

Progesterone receptor modulators can be prepared by thionation ofcarbonyl compounds. The thionation of benzoxazin-2-ones using either2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent) or phosphorous pentasulfide is known (U.S. Pat. No.6,436,929). See, Scheme 1.

Such compounds are useful for contraception, hormone replacementtherapy, synchronization of estrus, and in the treatment of conditionsincluding hormone neoplastic diseases, adenocarcinomas, and carcinomas.

However, certain impurities formed during thionation are difficult toremove. What is needed in the art are methods for reducing oreliminating the formation of impurities.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides methods for preventing,reducing or minimizing the formation of thioamide impurities.

In another aspect, the present invention provides methods forpreventing, reducing or minimizing the formation of thioamide impuritiesusing a decoy agent.

In a further aspect, the present invention provides methods forpreventing, reducing or minimizing the formation of thioamide impuritiesduring thionation of a carbonyl compound comprising a nitrile group.

In yet another aspect, the present invention provides methods forpreventing the formation of thioamide impurities of the structure,wherein Y, R⁷-R⁹ are defined below:

In still a further aspect, the present invention provides methods forpreventing the formation of thioamide impurities of the structure,wherein R¹, R⁷, and R⁸ are defined below:

In another aspect, the present invention provides methods for preventingthe formation of thioamide impurities of the structure, wherein R¹-R⁵are defined below:

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for minimizing the formation ofthioamide compounds using decoy agents. Specifically, the presentinvention provides methods for adding decoy agents to avoid undesirableside reactions.

I. Definitions

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1 to about10 carbon atoms, and desirably 1 to about 8 carbon atoms. The term“alkenyl” is used herein to refer to both straight- and branched-chainalkyl groups having one or more carbon-carbon double bonds andcontaining about 2 to about 10 carbon atoms. Desirably, the term alkenylrefers to an alkyl group having 1 or 2 carbon-carbon double bonds andhaving 2 to about 6 carbon atoms. The term “alkynyl” group is usedherein to refer to both straight- and branched-chain alkyl groups havingone or more carbon-carbon triple bond and having 2 to about 8 carbonatoms. Desirably, the term alkynyl refers to an alkyl group having 1 or2 carbon-carbon triple bonds and having 2 to about 6 carbon atoms.

The term “cycloalkyl” is used herein to refer to an alkyl group aspreviously described that is cyclic in structure and has about 4 toabout 10 carbon atoms, and desirably about 5 to about 8 carbon atoms.

The terms “substituted alkyl”, “substituted alkenyl”, “substitutedalkynyl”, and “substituted cycloalkyl” refer to alkyl, alkenyl, alkynyl,and cycloalkyl groups, respectively, having one or more substituents thesame or different including, without limitation, halogen, CN, OH, NO₂,amino, aryl, heterocyclic, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy,and arylthio which groups are optionally substituted. These substituentscan be attached to any carbon of an alkyl, alkenyl, or alkynyl groupprovided that the attachment constitutes a stable chemical moiety.

The term “aryl” as used herein as a group or part of a group refers toan aromatic system which can include a single ring or multiple aromaticrings fused or linked together where at least one part of the fused orlinked rings forms the conjugated aromatic system e.g. having 6 to 14carbon atoms. The aryl groups can include, but are not limited to,phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl,indene, benzonaphthyl, fluorenyl, and carbazolyl.

The term “substituted aryl” refers to an aryl group which is substitutedwith one or more substituents the same or different including halogen,CN, OH, NO₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, aminoalkyl, andarylthio, which groups can be optionally substituted. Desirably, asubstituted aryl group is substituted with 1, 2, 3 or 4 substituents.

The term “heterocyclic” or “heteroaryl” as used herein refers to astable 4- to 10-membered monocyclic or multicyclic heterocyclic ringwhich is saturated, partially unsaturated, or wholly unsaturated. Theheterocyclic ring has carbon atoms and one or more heteroatoms includingnitrogen, oxygen, and sulfur atoms. Desirably, the heterocyclic ring has1 to about 4 heteroatoms in the backbone of the ring. When theheterocyclic ring contains nitrogen or sulfur atoms in the backbone ofthe ring, the nitrogen or sulfur atoms can be oxidized. The term“heterocyclic” also refers to multicyclic rings in which a heterocyclicring is fused to an aryl ring e.g. of 6 to 14 carbon atoms. Theheterocyclic ring can be attached to the aryl ring through a heteroatomor carbon atom provided the resultant heterocyclic ring structure ischemically stable.

A variety of heterocyclic or heteroaryl groups are known in the art andinclude, without limitation, oxygen-containing rings,nitrogen-containing rings, sulfur-containing rings, mixedheteroatom-containing rings, fused heteroatom containing rings, andcombinations thereof. Oxygen-containing rings include, but are notlimited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinylrings. Nitrogen-containing rings include, without limitation, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, pyridyl, piperidinyl,2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfur-containingrings include, without limitation, thienyl and dithiolyl rings. Mixedheteroatom containing rings include, but are not limited to, oxathiolyl,oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, anddiazepinyl rings. Fused heteroatom-containing rings include, but are notlimited to, benzofuranyl, thionapthene, indolyl, benazazolyl,purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl,anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl, benzodiazonyl,napthylridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl, xanthenyl,acridinyl, and purinyl rings.

The term “substituted heterocyclic” or “substituted heteroaryl” as usedherein refers to a heterocyclic group having one or more substituentsthe same or different including halogen, CN, OH, NO₂, amino, alkyl,cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl,alkylcarboxy, aminoalkyl, and arylthio, which groups can be optionallysubstituted. Desirably, a substituted heterocyclic group is substitutedwith 1, 2, 3 or 4 substituents.

The term “alkoxy” as used herein refers to the O(alkyl) group, where thepoint of attachment is through the oxygen-atom and the alkyl group isoptionally substituted.

The term “aryloxy” as used herein refers to the O(aryl) group, where thepoint of attachment is through the oxygen-atom and the aryl group isoptionally substituted.

The term “alkyloxy” includes hydroxyalkyl and as used herein refers tothe alkylOH group, where the point of attachment is through the alkylgroup.

The term “arylthio” as used herein refers to the S(aryl) group, wherethe point of attachment is through the sulfur-atom and the aryl groupcan be optionally substituted.

The term “alkylcarbonyl” as used herein refers to the C(O)(alkyl) group,where the point of attachment is through the carbon-atom of the carbonylmoiety and the alkyl group is optionally substituted.

The term “alkylcarboxy” as used herein refers to the C(O)O(alkyl) group,where the point of attachment is through the carbon-atom of the carboxymoiety and the alkyl group is optionally substituted.

The term “aminoalkyl” includes alkylamino and as used herein refers toboth secondary and tertiary amines where the point of attachment isthrough the nitrogen-atom and the alkyl groups are optionallysubstituted. The alkyl groups can be the same or different.

The term “thioalkoxy” or “thioalkyl” as used herein refers to theS(alkyl), where the point of attachment is through the sulfur-atom andthe alkyl group is optionally substituted.

The term “halogen” as used herein refers to Cl, Br, F, or I groups.

The term “amide” as used herein refers to the C(O)NH₂ group, where thepoint of attachment is through the carbon-atom. Similarly, the term“thioamide” as used herein refers to a C(S)NH₂ substituent.

The term “nitrile” or “cyano” as used herein refers to a CN group.

The term “ketone” as used herein refers to the C(O) group, where thepoints of attachment are through the carbon-atom. Similarly, the term“aldehyde” as used herein refers to the C(O)H, where the point ofattachment is through the carbon-atom.

The term “lactone” as used herein refers to a ring having an estermoiety in the backbone of the ring. The lactone ring can be optionallysubstituted with any substituent that forms a stable bond to the ring.

The terms “carbamate” and “urethane” are used herein interchangeably torefer to a N—C(O)O group, where the point of attachments are through thenitrogen and oxygen atoms.

The term “carbonate” is used herein to refer to a O—C(O)—O group.

The term “enone” is used therein to refer to a molecule that contains analkene group, i.e., —C═C—, and a ketone group. Desirably, the enone isC═C—C(O), where the point of attachments are through the carbon-atom ofthe alkene and the carbon-atom of the carbonyl.

The term “enaminone” is used herein to refer to a molecule that containsthe —N—C═C—C(O) group, where the point of attachments are through thecarbon-atom of the alkene and the carbon-atom of the carbonyl.

The term “purified” or “pure” as used herein refers to a compound thatcontains less than about 10% impurity. Desirably, the term “purified” or“pure” refers to a compound that contains less than about 5% impurity,more desirably, less than about 2% impurity, and most desirably lessthan 1% impurity. The term “purified” or “pure” can also refer to acompound that contains about 0% impurity. In one embodiment, theimpurity is a thioamide.

II. The Decoy Agent

Methods are provided for preventing or minimizing the formation ofimpurities such as thioamides. Desirably, the present invention providesmethods for preventing or minimizing the formation of thioamideimpurities during thionations of carbonyl compounds containing nitrilegroups. The method utilizes a decoy agent containing a nitrile group.See, Scheme 2.

Without wishing to be bound by theory, the inventors have hypothesizedthat thioamide impurities are formed by addition of hydrogen sulfide(H₂S), a H₂S by-product, or a dithiaphosphetane by-product such as aLawesson's reagent by-product, among others, to a nitrite moiety. See,Scheme 3. Therefore, the inventors have found that the addition of adecoy agent in the reaction mixture that prevents or minimizes theformation of the thioamide impurity is advantageous.

The decoy agent used in the present invention competes with the nitritesubstituent of the carbonyl compound during thionation. In oneembodiment, the decoy agent competes with the nitrile substituent forreaction with H₂S, an H₂S by-product formed during the reaction, or aLawesson's agent by-product formed during thionation of a carbonylcompound having a nitrile compound attached thereto. However, the decoyagent desirably reacts only minimally or does not react with actualthionating reagent.

The term “decoy agent” as used herein is distinguishable from“scavengers”, “trapping agents” or “mopping reagents”. As known to thoseof skill in the art, scavengers, trapping agents or mopping reagents areused to remove excess reagents, products, or other formed impurities.For example, H₂S can be scavenged with lead acetate, trapped withmolecular sieves, or mopped with water. A decoy agent, however, isintentionally added to redirect any side reactions and is a sacrificialreagent which protects the product from being a source of a contaminant.

One of skill in the art would readily be able to select a suitable decoyagent depending on the reaction conditions, cost of decoy agent,reactivity of the decoy agent, reactivity of the carbonyl compound, andreactivity of the carbonyl group of the carbonyl compound. Desirably,the decoy agent is similar in structure to the nitrile group of thecarbonyl compound.

Electron withdrawing substituents attached to the decoy agent canincrease the reactivity of the decoy agent, and specifically, thereactivity of a nitrile group on the decoy agent. Desirably, theelectron withdrawing substituent includes a halogen, and more desirablychlorine. Desirably, the decoy agent is chloroacetonitrile (ClCH₂CN),trichloroacetonitrile, or 1,3-dicyanobenzene.

In one embodiment, the carbonyl compound contains a very reactivecarbonyl group and a less reactive nitrile group, whereby the carbonylgroup easily reacts with the thionating compound. In this case, a lessreactive decoy agent can be utilized during the thionation reaction toprevent formation of the thioamide impurity. However, more reactivedecoy agents can be utilized with reactive carbonyl compounds.Typically, acetonitrile is utilized if the carbonyl group of thecarbonyl compound easily reacts with the thionating agent.

In another embodiment, the carbonyl compound contains a reactivecarbonyl group and a reactive nitrile group. In this case, a moderatelyreactive decoy agent can be utilized during the thionation reaction toprevent formation of the thioamide impurity. Typically, moderatelyreactive decoy agents such as benzonitrile, p-chlorobenzonitrile,p-methylbenzonitrile, 1,3-dicyanobenzene, 3- and 4-cyanopyridines andmalononitrile can be utilized.

In a further embodiment, the carbon-containing compound contains a lessreactive carbonyl group and a highly reactive nitrile. In this case, ahighly reactive decoy agent can be utilized during the thionationreactive to prevent formation of the thioamide impurity. Typically,highly reactive decoy agents such as N-methyl-2-pyrrolecarbonitrile,2-thiophenecarbonitrile, 2-cyanopyridine, chloroacetonitrile andtrichloroacetonitrile can be utilized.

Examples of decoy agents that can be used according to the presentinvention include, without limitation, aryl nitrites includingbenzonitrile, p-chlorobenzonitrile, p-methoxybenzonitrile,p-ethoxybenzonitrile, o-nitrobenzonitrile, p-acetylbenzonitrile,p-methylbenzonitrile, p-fluorobenzonitrile, and 1,3-dicyanobenzene;aliphatic nitriles such as acetonitrile (CH₃CN), propionitrile,butyronitrile, iosbutyronitrile, chloroacetonitrile,trichloroacetonitrile and malononitrile; a nitrile compound having oneor more electron withdrawing substituents; or heteroaryl nitritesincluding N-methyl-2-pyrrolecarbonitrile, 2-thiophenecarbonitrile, and2-cyanopyridine. However, while some decoy agents may be utilized, itmay be cost-prohibitive for the use thereof. For example, CH₃CN is aninexpensive, low-boiling, common reagent with twice the moles of nitrilegroups as compared to N-methyl-2-pyrrolecarbonitrile. Further, while2-thiophenecarbonitrile is twice as reactive as benzonitrile, it isconsiderably more expensive. More desirably, the decoy agent is similarin structure to N-methyl-2-pyrrolecarbonitrile and is acetonitrile or2-thiophenecarbonitrile.

A molar excess of the decoy agent is typically added to the reactionmixture, where the reaction mixture contains a compound having a nitrilemoiety, i.e., moles of decoy agent are greater than moles of nitrilecompound. However, less than a 1:1 ratio of decoy agent to the compoundhaving a nitrile moiety, i.e., moles of decoy agent are less than molesof nitrile compound, can also be utilized. In one embodiment, greaterthan an about 10 molar excess of decoy agent is utilized. In anotherembodiment, greater than an about 20 molar excess; in a furtherembodiment, greater than an about 40 molar excess; and in still anotherembodiment, greater than a 100 molar excess of decoy agent is utilized.In one embodiment, the decoy agent can be utilized as the solvent. Oneof skill in the art would readily be able to determine the amount ofdecoy agent required depending on the reaction being performed, reagentsutilized, and reactivity of the decoy agent.

III. The Method of the Invention

The present invention thereby provides methods for preventing orminimizing the formation of thioamide impurities. Typically, thethioamide impurities formed according to the present invention includethioamide groups attached at any location on the backbone of thethioamide molecule.

In one embodiment, the thioamide impurity contains a thioamide group ofthe structure:

In another embodiment, the thioamide impurity is of the structure:

wherein Y is O or S; R⁷ is H, NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substitutedC₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ toC₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R⁸ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; or R⁷ and R⁸ are fused to form (i) asaturated carbon-based 4 to 8 membered ring; (ii) an unsaturatedcarbon-based 4 to 8 membered ring; or (iii) a 4 to 8 heterocyclic ringcontaining 1 to 3 heteroatoms selected from among O, N, and S; whereinrings (i)-(iii) are optionally substituted by 1 to 3 substituentsselected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ toC₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substitutedC₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ to C₆ aminoalkyl, and substitutedC₁ to C₆ aminoalkyl; R⁹ is absent, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl,substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; R¹⁰ is selectedfrom among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl,substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, NH₂, NHR¹¹, and N(R¹¹)₂; and R¹¹ isselected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl,substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, and NH₂.

In a further embodiment, the thioamide impurity is of the structure:

or a combination thereof,wherein, R⁷ is H, NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R⁸ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; or R⁷ and R⁸ are fused to form (i) asaturated carbon-based 4 to 8 membered ring; (ii) an unsaturatedcarbon-based 4 to 8 membered ring; or (iii) a 4 to 8 heterocyclic ringcontaining 1 to 3 heteroatoms selected among O, N, and S; wherein rings(i)-(iii) are optionally substituted by 1 to 3 substituents selectedfrom among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ to C₆ aminoalkyl, and substitutedC₁ to C₆ aminoalkyl; R⁹ is absent, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl,substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; R¹⁰ is selectedfrom among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl,substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, NH₂, NHR¹¹, and N(R¹¹)₂; and R¹¹ isselected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl,substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, and NH₂.

In still a further embodiment, the thioamide impurity contains athioamide group that is attached to a pyrrole ring or to a substituentof a pyrrole ring. The thioamide impurity can therefore have thefollowing thioamide substituent, where R¹ is C₁ to C₆ alkyl orsubstituted C₁ to C₆ alkyl.

In another embodiment, the thioamide impurity is of the structure:

wherein, R¹ is selected from among C₁ to C₆ alkyl or substituted C₁ toC₆ alkyl. and R⁷ and R⁸ are defined above.

In still a further embodiment, the thioamide impurity is of thestructure:

wherein, R¹ is selected from among C₁ to C₆ alkyl or substituted C₁ toC₆ alkyl. R² and R³ are independently selected from among H, C₁ to C₆alkyl, or substituted C₁ to C₆ alkyl; or R² and R³ are fused to form aring including —CH₂(CH₂)_(n)CH₂—, —CH₂CH₂C(CH₃)₂CH₂CH₂—,—O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—, or —CH₂CH₂NR⁶CH₂CH₂—, nis 1, 2, 3, 4, or 5, p is 1, 2, 3, or 4, and q is 1, 2, 3, or 4; R⁴ isselected from among H, OH, NH₂, CN, halogen, C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆alkynyl, or substituted C₂ to C₆ alkynyl; R⁵ is selected from among H,C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substitutedC₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆aminoalkyl; R⁶ is selected from among H or C₁ to C₆ alkyl; Q is selectedfrom among O or S; and X is absent or is selected from among O or S.

In still a further embodiment, the thioamide impurity is of thestructure:

wherein, R¹-R⁵, X, and Q are defined above.

The carbonyl compound containing a nitrile group utilized in the presentinvention contains at least one carbonyl and at least one nitrile group.The present invention also provides for carbonyl compounds having morethan 1 carbonyl group, e.g., 2, 3, 4, 5, or 5 carbonyl groups and more,more than 1 nitrile group, e.g., 2, 3, 4, or 5 nitrile groups and more,or a combination thereof.

In one embodiment, the carbonyl compound is of the structure:

wherein, R⁷ is H, NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R⁸ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; or R⁷ and R⁸ are fused to form (i) asaturated carbon-based 4 to 8 membered ring; (ii) an unsaturatedcarbon-based 4 to 8 membered ring; or (iii) a 4 to 8 heterocyclic ringcontaining 1 to 3 heteroatoms selected from among O, N, and S; whereinrings (i)-(iii) are optionally substituted by 1 to 3 substituentsselected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ toC₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substitutedC₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ to C₆ aminoalkyl, and substitutedC₁ to C₆ aminoalkyl; R⁹ is absent, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl,substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; R¹⁰ is selectedfrom among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl,substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, NH₂, NHR¹¹, and N(R¹¹)₂; and R¹¹ isselected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl,substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, and NH₂.

In a further embodiment, the carbonyl compound is of the structure:

wherein, R¹ is C₁ to C₆ alkyl or substituted C₁ to C₆ alkyl; R⁷ and R⁸are defined above.

In yet another embodiment, the carbonyl compound is of the structure:

wherein, R¹ is C₁ to C₆ alkyl or substituted C₁ to C₆ alkyl; R² and R³are, independently, H, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; orR² and R³ are fused to form a ring comprising —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—,or —CH₂CH₂NR⁶CH₂CH₂—; n is 1 to 5; p is 1 to 4; q is 1 to 4; R⁴ is H,OH, NH₂, CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ toC₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, orsubstituted C₂ to C₆ alkynyl; R⁵ is H, C₁ to C₆ alkyl, substituted C₁ toC₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl; R⁶ is H or C₁ to C₆alkyl; X is O, S, or absent; or a pharmaceutically acceptable saltthereof.

In still a further embodiment, the carbonyl compound is of thestructure:

wherein, R¹-R⁵ and X are defined above.

Typically, the decoy agent utilized is in the presence of a solvent. Oneof skill in the art would readily be able to select a suitable solventfor use with the decoy agent depending on the other reagents utilizedand reaction conditions, among others. Desirably, the solvent does notreact with any of the reagents utilized in the reaction and does notcontain any peroxides. In one embodiment, the solvent includestetrahydrofuran (THF), 1,2-dimethoxyethane (DME), toluene, and methylenechloride, among others.

The decoy agent can be utilized at any temperature that facilitates thereaction and can readily be determined by one of skill in the art.Desirably, the decoy agent is utilized at least room temperature, andmore desirably at the boiling point of the solvent.

When the decoy agent is utilized in a thionation reaction, the reactionis performed using a thionating agent. Several thionating agents thatreplace O-atoms with S-atoms are known in the art and include, withoutlimitation, phosphorus pentasulfide (P₄S₁₀), hydrogen sulfide,Lawesson's reagent, and dialkyldithiophosphates such asdiethyldithiophosphate (See, Phosphorous and Sulfur 1985, 25, 297). See,Scheme 4.

Desirably, the thionating agent does not react with the decoy reagent.The thionation can also be performed with thionating by-products thatagents are formed during the reaction and include:

In one embodiment, the present invention provides a method forpreventing or minimizing the formation of thioamide impurities duringthionation of a nitrile compound containing a carbonyl group includingperforming the thionation in the presence of a decoy agent having anitrile group.

In another embodiment, the present invention provides a product preparedby the method of the present invention.

The resulting compounds of the present invention can be formulated in aphysiologically compatible carrier and used as PR modulators asdescribed in U.S. Pat. Nos. 6,509,334; 6,391,907; 6,417,214; and6,407,101, which are hereby incorporated by reference. The inventionfurther provides kits comprising the product.

The following examples are provided to illustrate the invention and donot limit the scope thereof. One skilled in the art will appreciate thatalthough specific reagents and conditions are outlined in the followingexamples, modifications can be made which are meant to be encompassed bythe spirit and scope of the invention.

EXAMPLES Example 1 Reactivity of Decoy Agents

One mmol of the aromatic nitrile decoy agents set forth in Table 1 werereacted at reflux with the thionating agent diethyl dithiophosphate (0.2mL) in wet THF (6 mL) to give the respective thioamides.

TABLE 1 Nitrile % Conversion to Thioamide* 2-thiophenecarbonitrile 100 benzonitrile 55 p-chlorobenzonitrile 67 p-methoxybenzonitrile 45o-nitrobenzonitrile 25 p-acetylbenzonitrile 57 p-methylbenzonitrile 52p-fluorobenzonitrile 68 * % conversion as determined by gaschromatography/mass spectroscopy (GC/MS)

This example illustrates that 2-thiophenecarbonitrile was the mostreactive with the thionating agent.

Example 2 Use of Decoy Agent During Thionation

Acetonitrile (21 kg, 512 mol) was utilized as decoy agent in athionation of5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(34 kg, 126 mol), i.e., a 4:1 molar ratio, using Lawesson's reagent(28.3 kg, 70 mol) in DME (505 kg) at reflux to give5-(4,4-dimethyl-2-thioxo-1,4-dihydro-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(26.7 kg; 74% yield).

The crude reaction mixture of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrilecontained only about 2.6% of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-benzoxazine)-1-methyl-pyrrole-2-thioamideimpurity. After recrystallization, the purified5-(4,4-dimethyl-2-thioxo-1,4-dihydro-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrilewas about 99.90% pure.

When the reaction was performed in the absence of the decoy agent, thethioamide impurity was present at about 11 to about 12%.

Example 3 Competition Between 2-Thiophenecarbonitidle and Alkyl Nitriles

2-Thiophenecarbonitrile (1 mmol) was reacted at reflux with diethyldithiophosphate (200 μL) in wet THF (6 mL) and in the presence of thealiphatic nitrites (1 mmol) set forth in Table 2. The conversion of theundesired thiophene-2-carbothioic acid amide was then measured.

TABLE 2 Nitrile % Conversion to Thioamide* None 75 Trichloroacetonitrile46 Chloroacetonitrile 40 Malononitrile 54 Acetonitrile 71 *Technicalgrade of diethyldithiophosphate was utilized.

This example illustrates that conversion of a reactive nitrile, such as2-thiophene carbonitrile, to the thioamide impurity is high when nodecoy agent is utilized. However, conversion to the thioamide impurityis decreased when decoy agents are utilized.

Example 4 Competition Between 2-Thiophenecarbonitrile and Acetonitrile

2-Thiophenecarbonitrile (1 mmol) was reacted at reflux with diethyldithiophosphate (200 μL) in wet THF and acetonitrile using the molarequivalents set forth in Table 3. The conversion of the undesiredthiophene-2-carbothioic acid amide was then measured.

TABLE 3 Molar Equivalent of Acetonitrile % Conversion to Thioamide  1 7110 53 20 37 40 25 120** 19 *Volume of THF and MeCN retained at 6 mL byadjusting the amount of MeCN and THF. **Neat acetonitrile (no THFsolvent present)

This example illustrates that conversion to the thioamide impuritydecreased as the amount of acetonitrile increased.

Example 5 Effect of Acetonitrile on the Formation of ThioamideImpurities

The nitrile set forth in Table 4 was reacted at reflux with diethyldithiophosphate (200 μL) in wet THF (5 mL) and acetonitrile (1 mL=20molar equivalents). The control set contained 6 mL THF and noacetonitrile. After 5 hours at 66° C., the mixtures were subjected toGC/MS analysis to detect the presence of thioamide impurity.

TABLE 4 % Conversion to Thioamide Nitrile with acetonitrile withoutacetonitrile 2-thiophenecarbonitrile 33 78 benzonitrile 11 43p-acetylbenzonitrile 11 45 p-methoxybenzonitrile  2 38p-chlorobenzonitrile 13 51 1,4-dicyanobenzene 34 67

This example illustrates that conversion to the thioamide impurity wassuppressed in samples containing acetonitrile. Further, samplescontaining acetonitrile and p-methoxybenzonitrile had very littleconversion to the thioamide impurity.

Example 6 Use of Decoy Agent During Thionation

A 2-L flask was charged with 1,2-dimethoxyethane (2.1 L) and5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-oxo-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile(150 g, 0.49 mol), followed by Lawesson's reagent (119 g, 0.295 mol) andacetonitrile (0.3 L, 5.75 mol), i.e., a 12:1 molar ratio of decoy agentto nitrile compound. The suspension was heated to reflux and kept for 1hour. Upon cooling to ambient temperature, water (2.51 L) was added tothe suspension at a rate to maintain the temperature below 30° C. Theyellow-greenish precipitate was filtered on a fritted funnel. The solidwas transferred back to the reaction flask and slurried in water (0.75L) overnight. The yellow suspension was filtered, washed with water(0.45 L) and dried to give 154 g (98% yield, 99.0% purity by HPLC area,mp 269-271.5° C., 0.60% thioamide impurity) of5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile.

Example 7 Use of Decoy Agent During Thionation (Scale-Up)

In this example, a larger scale production of[5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile]was performed.

A 100-gal vessel was charged with 1,2-dimethoxyethane (155.1 kg, 178.8L) and5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-oxo-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile(12.78 kg), followed by Lawesson's reagent (10.14 kg) and acetonitrile(20.1 kg, 25.6 L). The contents of the vessel was heated to reflux andkept for 1 hour. The orange-brown solution was cooled to 70° C. and asample was withdrawn for the reaction completion test that showed lessthan 0.2% of the starting material. The batch was cooled to ambienttemperature and water (213.9 kg) was charged at a rate to maintaintemperature between 23 and 29° C. The yellow-greenish suspension wasfiltered on a 0.3 SQM PSL filter/dryer. The solids were slurried inwater (63.9 kg) on the filter/dryer for 15 minutes. The yellowsuspension was transferred into a 100-gal vessel and the filter wasrinsed with water (2×10 kg) into the vessel. The slurry was stirred at18-26° C. for 12 hours, filtered on a 0.3 SQM PSL filter/dryer andwashed with water (2×19.2 kg). The solids were dried in a vacuum oven atinitially 20-30° C. and then at 45° C. to give 12.8 kg of crude5-(2′-thioxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-1H-pyrrole-2-carbonitrile(95% yield, 0.45% thioamide impurity).

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A method for preventing, reducing or minimizing the formation ofthioamide impurities during thionation of a carbonyl compound comprisinga nitrile group, comprising performing said thionation in the presenceof a decoy agent comprising a nitrile group.
 2. The method according toclaim 1, wherein the moles of said decoy agent is greater than the molesof said carbonyl compound.
 3. The method according to claim 1, whereinthe moles of said decoy agent is less than the moles of said carbonylcompound.
 4. The method according to claim 1, wherein said thioamideimpurity is of the structure:

wherein: Y is O or S; R⁷ is H, NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substitutedC₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ toC₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R⁸ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; or R⁷ and R⁸ are fused to form: (i) asaturated carbon-based 4 to 8 membered ring; (ii) an unsaturatedcarbon-based 4 to 8 membered ring; or (iii) a 4 to 8 heterocyclic ringcontaining 1 to 3 heteroatoms selected from the group consisting of O,N, and S; wherein rings (i)-(iii) are optionally substituted by 1 to 3substituents selected from the group consisting of H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆aminoalkyl; R⁹ is absent, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl,substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; R¹⁰ is selectedfrom the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, aryl, substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆thioalkyl, substituted C₁ to C₆ thioalkyl, NH₂, NHR¹¹, and N(R¹¹)₂; andR¹¹ is selected from the group consisting of H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, aryl, substituted aryl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆aminoalkyl, C₁ to C₆ thioalkyl, substituted C₁ to C₆ thioalkyl, and NH₂.5. The method according to claim 4, wherein said thioamide impurity isof the structure:

wherein: R¹ is C₁ to C₆ alkyl or substituted C₁ to C₆ alkyl; R⁷ is H,NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁ to C₆ alkyl, substituted C₁ toC₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl, substituted C₁ to C₆ thioalkyl,C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R⁸ is C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; or R⁷ and R⁸are fused to form: (i) a saturated carbon-based 4 to 8 membered ring;(ii) an unsaturated carbon-based 4 to 8 membered ring; or (iii) a 4 to 8heterocyclic ring containing 1 to 3 heteroatoms selected from the groupconsisting of O, N, and S; wherein rings (i)-(iii) are optionallysubstituted by 1 to 3 substituents selected from the group consisting ofH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆aminoalkyl; R¹⁰ is selected from the group consisting of H, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁to C₆ aminoalkyl, C₁ to C₆ thioalkyl, substituted C₁ to C₆ thioalkyl,NH₂, NHR¹¹, and N(R¹¹)₂; and R¹¹ is selected from the group consistingof H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substitutedaryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl,substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl, substituted C₁ toC₆ thioalkyl, and NH₂.
 6. The method according to claim 4, wherein saidthioamide impurity is of the structure:

wherein: R¹ is C₁ to C₆ alkyl or substituted C₁ to C₆ alkyl; R² and R³are, independently, H, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; orR² and R³ are fused to form a ring comprising —CH₂(CH₂)_(n)CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—,or —CH₂CH₂NR⁶CH₂CH₂—; n is 1 to 5; p is 1 to 4; q is 1 to 4; R⁴ is H,OH, NH₂, CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ toC₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, orsubstituted C₂ to C₆ alkynyl; R⁵ is H, C₁ to C₆ alkyl, substituted C₁ toC₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl; R⁶ is H or C₁ to C₆alkyl; Q is O or S; X is O, S, or absent; or a pharmaceuticallyacceptable salt thereof.
 7. The method according to claim 1, whereinsaid carbonyl compound is a ketone, enone, aldehyde, ester, lactone,amide, carbamate, carbonate, or enaminone.
 8. The method according toclaim 7, wherein said carbonyl compound is of the structure:

wherein: R⁷ is H, NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl,substituted C₁ to C₆ thioalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R⁸ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; or R⁷ and R⁸ are fused to form: (i) asaturated carbon-based 4 to 8 membered ring; (ii) an unsaturatedcarbon-based 4 to 8 membered ring; or (iii) a 4 to 8 heterocyclic ringcontaining 1 to 3 heteroatoms selected from the group consisting of O,N, and S; wherein rings (i)-(iii) are optionally substituted by 1 to 3substituents selected from the group consisting of H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆aminoalkyl; R⁹ is absent, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl,substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; R¹⁰ is selectedfrom the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, aryl, substituted aryl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆ aminoalkyl, C₁ to C₆thioalkyl, substituted C₁ to C₆ thioalkyl, NH₂, NHR¹⁰, and N(R¹¹)₂; andR¹¹ is selected from the group consisting of H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, aryl, substituted aryl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆aminoalkyl, C₁ to C₆ thioalkyl, substituted C₁ to C₆ thioalkyl, and NH₂.9. The method according to claim 7, wherein said carbonyl compound is ofthe structure:

wherein: R¹ is C₁ to C₆ alkyl or substituted C₁ to C₆ alkyl; R⁷ is H,NH₂, NHR¹⁰, N(R¹⁰)₂, C(O)R¹⁰, C(S)R¹⁰, C₁ to C₆ alkyl, substituted C₁ toC₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, C₁ to C₆ thioalkyl, substituted C₁ to C₆ thioalkyl,C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R⁸ is C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; or R⁷ and R⁸are fused to form: (i) a saturated carbon-based 4 to 8 membered ring;(ii) an unsaturated carbon-based 4 to 8 membered ring; or (iii) a 4 to 8heterocyclic ring containing 1 to 3 heteroatoms selected from the groupconsisting of O, N, and S; wherein rings (i)-(iii) are optionallysubstituted by 1 to 3 substituents selected from the group consisting ofH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆aminoalkyl; R¹⁰ is selected from the group consisting of H, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, C₁ to C₆alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁to C₆ aminoalkyl, C₁ to C₆ thioalkyl, substituted C₁ to C₆ thioalkyl,NH₂, NHR¹¹, and N(R¹¹)₂; and R¹¹ is selected from the group consistingof H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substitutedaryl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl,substituted C₁ to C₆ aminoalkyl, C₁ to C₆ thioalkyl, substituted C₁ toC₆ thioalkyl, and NH₂.
 10. The method according to claim 7, wherein saidcarbonyl compound is of the structure:

wherein: R¹ is C₁ to C₆ alkyl or substituted C₁ to C₆ alkyl; R² and R³are, independently, H, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; orR² and R³ are fused to form a ring comprising —CH₂(CH₂),CH₂—,—CH₂CH₂C(CH₃)₂CH₂CH₂—, —O(CH₂)_(p)CH₂—, —O(CH₂)_(q)O—, —CH₂CH₂OCH₂CH₂—,or —CH₂CH₂NR⁶CH₂CH₂—; n is 1 to 5; p is 1 to 4; q is 1 to 4; R⁴ is H,OH, NH₂, CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ toC₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, orsubstituted C₂ to C₆ alkynyl; R⁵ is H, C₁ to C₆ alkyl, substituted C₁ toC₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl; R⁶ is H or C₁ to C₆alkyl; X is O, S, or absent; or a pharmaceutically acceptable saltthereof.
 11. The method according to claim 1, wherein said decoy agentis similar in structure to the nitrile group in said carbonyl compound.12. The method according to claim 1, wherein said decoy agent isacetonitrile.
 13. The method according to claim 1, wherein said decoyagent comprises an electron withdrawing substituent.
 14. The methodaccording to claim 13, wherein said decoy agent is chloroacetonitrile ortrichloroacetonitrile.
 15. The method according to claim 1, wherein saiddecoy agent is an aryl nitrile selected from the group consisting ofbenzonitrile, p-chlorobenzonitrile, p-methoxybenzonitrile,p-ethoxybenzonitrile, o-nitrobenzonitrile, p-acetylbenzonitrile,p-methylbenzonitrile, p-fluorobenzonitrile, and 1,3-dicyanobenzene. 16.The method according to claim 1, wherein said decoy agent is aheteroaryl nitrile selected from the group consisting ofN-methyl-2-pyrrolecarbonitrile, 2-thiophenecarbonitrile,2-cyanopyridine, 3-cyanopyridine and 4-cyanopyridine.
 17. The methodaccording to claim 1, wherein said thionation is performed with athionating agent selected from the group consisting of hydrogen sulfide,Lawesson's reagent, phosphorus pentasulfide, and diethyldithiophosphate.